Genetic and genomic studies have identified genes and gene
variants that potentially modulate the fundamental biological mechanisms
underpinning addictive processes. Discovery of these genes/variants, while
extremely valuable, is only a first step in understanding molecular
mechanisms of addiction. This Funding Opportunity Announcement encourages
basic functional genetic and genomic research in two areas: 1. functional
validation to determine which candidate genes/variants/epigenetic/non-coding
RNA features have an authentic role in addictive processes, and 2. detailed
elucidation of the molecular pathways and processes modulated by candidate
genes/variants, particularly for those genes with an unanticipated role in
addiction.

Key Dates

Posted Date

December 5, 2013

Open Date (Earliest Submission Date)

January 16, 2014

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

Standard
dates apply, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate
time to make any corrections to errors found in the application during the
submission process by the due date.

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any program-specific
instructions noted in Section IV. When
the program-specific instructions deviate from those in the Application Guide,
follow the program-specific instructions. Applications that do not
comply with these instructions may be delayed or not accepted for review.

There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. You can download an application package from Grants.gov, complete the forms offline, submit the completed forms to Grants.gov and track your application in eRA Commons. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons. Learn more.

Genetic and genomic studies have identified genes and gene
variants that potentially modulate the fundamental biological mechanisms
underpinning addictive processes. Discovery of these genes/variants, while
extremely valuable, is only a first step in understanding molecular mechanisms
of addiction. This Funding Opportunity Announcement (FOA) encourages basic
functional genetic and genomic research in two areas: 1. functional validation
to determine which candidate genes/variants/epigenetic/non-coding RNA features
have an authentic role in addictive processes, and 2. detailed elucidation of
the molecular pathways and processes modulated by candidate genes/variants,
particularly for those genes with an unanticipated role in addiction.

Background

Genes. Addiction to, or dependence on, drugs of abuse
(including prescription drugs, nicotine, methamphetamine, cannabis, opioids,
stimulants, and inhalants) is a major public health and economic problem.
Candidate genes/variants that play a role in addictive processes have been
identified using methods such as human or animal genome-wide association scans,
QTL characterization, gene expression profiling, forward or reverse genetic
screens, proteomics, or through epigenomic analyses. Genes and variants
identified by these methods are priority targets for functional validation.
Other candidate genes/variants include genes relevant to co-occurring
psychiatric disorders and social behaviors relevant to drug addiction, as well
as genes relevant to other areas of NIDA’s mission, including pain and HIV/AIDS
susceptibility and progression.

Functional Validation. The most desirable functional
validation would be demonstration of an epigenetic or genetic variant’s effect
on a human phenotype relevant to addiction. Effects of copy number variation,
modified chromatin states, methylation patterns, higher order chromatin
structure, transcriptional regulation and how these changes are influenced by
genetic variation are of interest. An epigenetic or genetic variant could
manifest itself phenotypically at the level of a molecular pathway, cell,
circuit, organism, or social interaction, leading to phenotypic differences in
protein function, cell morphology, neural connectivity, behavioral responses to
an addictive drug, or behavioral responses to social cues. Validation studies
are encouraged at any of these levels to identify phenotypic differences
relevant to addictive processes and further elucidate the driving molecular
pathways that converge to elicit biobehavioral changes. Some human functional
validation studies may not be feasible or ethical, necessitating the use of in
vivo animal models or in vitro strategies.

Resources. There are numerous public and private resources
available to facilitate functional validation of genes/variants involved in
addiction. NIDA promotes the mining of databases (containing information such
as model organism phenotypes, physically interacting proteins, Roadmap
Epigenomics Program and ENCODE datasets, eQTL data, and gene expression levels
with respect to brain anatomy) to obtain insight into the molecular mechanisms
of epigenetic or genetic variant function in addictive processes. Publicly
available mutants in yeast, C. elegans, Drosophila, zebrafish, mouse, and other
models can be used for functional tests. For example, to test hypotheses about
gene function and addiction, the Knock Out Mouse Project (KOMP) provides ES
cells that can be used to generate knockout animals. Reagents for RNA
knockdown of genes are available for functional validation studies.
Researchers may also exploit iPS cells, human tissue banks, and post-mortem
tissue collections for validation studies. For many available resources see
Neuroscience Information Framework (http://www.neuinfo.org/).

Potential Research Areas and Approaches

Applicants proposing to functionally validate genetic
findings or to elucidate functional mechanisms for putative substance abuse
relevant genes are encouraged to apply to this FOA. Applicants proposing high
risk/high payoff exploratory/developmental research projects with limited preliminary
data are encouraged to submit an R21 grant application through this FOA, while
applicants proposing discrete projects with substantial preliminary data are
encouraged to submit an R01 grant application using the companion FOA. Applicants
proposing to discover new genes or gene variants involved in substance abuse
may also apply using the related NIDA FOA "Discovering Novel Targets: The
Molecular Genetics of Drug Addiction and Related Co-Morbidities."
Applications to this FOA can vary greatly in depth and breadth of analysis.
They may investigate a single high priority epigenetic or genetic variant in
detail (e.g. using transgenic mouse approaches) or test several hundred
genes/variants rapidly (e.g. using high throughput RNA knockdown).

NIDA seeks to understand addiction to abused substances such
as prescription drugs, nicotine, methamphetamine, cocaine, cannabis, opioids,
and inhalants. Applicants should therefore focus on one or more NIDA-relevant
substances of abuse. Applicants proposing to investigate alcohol in concert
with one or more NIDA-relevant drugs may also submit their CRAN-related project
to this FOA, since NIDA is a member of the Collaborative Research Activity on
Addiction at NIH (CRAN). Applicants investigating only the effects of alcohol
should submit using an appropriate NIAAA FOA.

The following list highlights some areas of functional
genetic/genomic research that would be of interest.

Human Studies. Functional validation studies could use
human DNA samples from phenotypically well-characterized individuals to
correlate a gene variant with a particular phenotype and/or endophenotype.
Similarly, post-mortem tissue could be used for allele-specific gene
expression, epigenomic mapping, or other studies. Researchers performing
assays that measure epigenomic or somatic genomic features are encouraged to
focus on tissues directly relevant to the disease being investigated. Some
applicants may wish to propose epigenomic investigations of blood to identify
potential biomarkers for chronic exposure to abused substances or as a
potential indicator of addiction trajectory. For blood studies, it may be
prudent to propose to collect multiple samples over time from the same
individual and to consider assaying only the most relevant cell type(s)
contained within the sample. Induced pluripotent stem cells (iPS cells) and
neurons or other cell types derived from these cells may be useful for
investigating the function of a genetic variant.

Comparison of Wild type and Gene Variant Functions. The
molecular alteration associated with a gene variant frequently does not reveal
whether the function of a particular gene is increased, decreased, or leads to
unexpected functional consequences. Yet this information is critical if one
wishes to exploit a gene variant to develop a therapeutic approach. Approaches
using in vivo transgenes, in vitro biochemical assays, or other validation
methods that can address these issues will help to identify the most promising
molecular targets for therapeutic interventions to treat addictions.

Addictive behavior. Approaches that can ascribe a
functional role to an epigenetic and/or genetic variant with respect to a
particular aspect of addictive behavior (e.g. drug reinforcement, tolerance,
withdrawal, craving, reinstatement) are of great interest, as are strategies to
identify epigenetic and/or genetic variant effects on behavioral responses to
other drugs or addictive stimuli, stress, changes in social situations, food,
other natural rewards, or other environmental stimuli. In general, applicants
are advised to carefully consider their selection of a behavioral model of drug
exposure or addiction and to justify why this behavioral model is the most
compelling choice for the proposed aims of their application.

Genetic Models. Established genetic models (such as yeast,
C. elegans, sea slug, Drosophila, zebrafish, mouse, and primate) as well as
emerging genetic models (such as rat) can be used to examine in vivo epigenetic
and/or genetic variant function. Strategies could include exploitation of
available genetic knockouts or other mutants, knockin of gene variants, or
conditional reduction or overexpression of wild type and variant alleles.
Since some model organism genomes (e.g. C. elegans and Drosophila) do not
encode obvious opioid or cannabinoid receptors, functional validation studies
involving these pathways would need to use genetic models such as zebrafish or
mouse. Cross-species validation of functional alleles is encouraged, as are studies
investigating sex differences with respect to epigenetic and/or genetic variant
function. Functional validation approaches that could lead to the development
of in vivo models of addictive processes or could facilitate future screening
for therapeutic agents are of great interest.

Genomic Manipulation. Depletion of candidate gene mRNAs in
cells, tissues, brain regions, or whole organisms using RNA interference or
related approaches can be used to discover or validate phenotypes. These
phenotypes could range from the cellular (e.g. changes in morphology or
function of synapses, dendritic spines, or neurons) to the organismal (e.g.
changes in behavioral responses to drugs). Similarly, applicants may wish to
exploit locus-specific genome editing approaches such as the use of TALE,
CRISPR or related strategies to address genetic or epigenetic function.
Strategies to investigate the effects of genetic or epigenetic variants in
specific cell types or during specific temporal windows using opto-epigenetic
or chemo-epigenetic approaches are also encouraged.

Epigenetics and Epigenomics. Identification of cell
type-specific epigenomic features associated with addictive processes as well
as functional validation of epigenetic mechanisms of gene regulation in the
context of neuroscience or addiction biology are encouraged as are studies
aiming to discover or better characterize histone or DNA modifications
important for neuronal signal transduction or regulation of gene expression.
Exploitation of chromatin structure assays (e.g. Hi-C, ChIA-PET) or microscopy
techniques to explore chromatin dynamics in response to substances of abuse are
also of interest.

Somatic Genomic Variation and Regulatory Elements. Studies
investigating somatic genomic variation and its regulation and function in the
nervous system and in response to drugs of abuse (including the role of
repetitive DNA, retrotransposons, and other sources of somatic genomic
variation as well as their potential functional effects on gene expression,
alternative splicing, or chromatin state) are encouraged. Studies exploiting
artificial somatic genomic variation such as DNA barcoding to tag brain cells
for cell censuses, connectivity studies, or functional characterization are
also of interest. Studies to assign drug abuse-related function to variants in
non-coding RNAs, microRNAs, gene regulatory elements, transposable elements, or
other putative non-protein coding regions of the genome are appropriate.

Non-coding RNAs and RNA Modifications. Studies to identify
and characterize non-coding RNAs relevant to neuroscience and addictive
processes are encouraged. Applicants might wish to investigate the role of
miRNA regulation in substance abuse, especially the identification of miRNA
targets and associated mechanistic pathways. Investigations into novel and
poorly understood classes of regulatory non-coding RNAs such as circular RNAs
(circRNAs), long non-coding RNAs (lncRNAs), or RNAs associated with chromatin
are of great interest. Applications investigating the potential functional
roles of RNA modifications in mRNAs or regulatory RNAs in the nervous system
are also encouraged.

Systems-level Approaches. Bioinformatic resources can be
mined to identify causal genes or gene variants or to generate testable
hypotheses concerning the function of candidate genes and groups of genes.
Some data types that could be used include: gene expression, epigenomic,
transcription factor binding information, proteomic, metabolomic, interactome,
functional genomic, in silico mapping data, connectome, or neuroanatomical
expression. Studies could test to see if sets of candidate disease genes are
co-expressed in a particular brain region or cell type, or function together in
a signal transduction cascade.

Cellular or Circuit-level Approaches. Studies comparing
epigenetic and/or genetic variant functional consequences at the cellular and
circuit levels, especially with respect to drug challenge are encouraged. Such
outcomes may include, but are not limited to, studies of differences in
neurotransmission, intracellular trafficking of proteins or RNAs,
neurophysiology, signal transduction, as well as synaptic and dendritic
physiology or morphology. Functional responses to changes in the neural
environment due to steroid hormones, cytokines and chemokines, neuropeptides or
neurotransmitter imbalance are also sought.

Developmental and Transgenerational Studies. Investigations
into the functional effects of genes/variants on organism development in the
context of drug exposure and addiction pathways are also of great interest.
Approaches investigating epigenetic and/or genetic variant roles in neuronal
differentiation, brain patterning, circuit formation, plasticity of brain
circuitry during adolescence, gene x environment, gene x development, or gene x
environment x development functional effects are all appropriate. In addition,
there are some indications that parental exposure to certain drugs of abuse may
lead to transgenerational phenotypic effects. Studies exploring these effects,
including whether or not these effects are inherited through epigenetic or
non-epigenetic mechanisms, are encouraged.

Imaging Strategies. Studies to identify in vivo human or
animal gene/variant/epigenetic effects on neuronal activity or brain functions
relevant to addiction are appropriate. These may include specific behaviors
associated with addictive processes that are influenced by neurocircuitry or
neuroconnectivity that may be assessed by imaging techniques such as fMRI, DTI,
MRS, or PET. Studies in live, behaving animals that examine brain function in
response to commonly abused drugs are encouraged, especially in animal models
of adolescent drug exposure.

Extracellular Vesicles. Secreted extracellular vesicles
(EVs) such as exosomes and microvesicles play an important role in many
biological processes. EVs appear to play several interesting roles in the
nervous system and may function in 1. neuronal-glial communication, 2. synaptic
plasticity, and 3. immune surveillance. Potential studies could include: 1.
the functional role of EVs and their cargoes in the nervous system,
particularly with respect to neuroplastic processes and substance abuse
exposures, 2. whether or not EVs in serum, cerebral spinal fluid, or other body
fluids might be useful biomarkers for substance abuse exposure or addiction
trajectory, and 3. whether or not EVs might have therapeutic utility for
cell-specific treatment of substance abuse.

Translational. The use of functionally validated gene
variants, RNAs, or proteins for clinical applications or as validated
biomarkers to predict phenotypes are of interest, as is the development of
cell-type specific targeting approaches to deliver DNA, RNA, protein or other
potentially therapeutic cargoes.

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National
Institute on Drug Abuse: In light of recent significant advances in rapid
testing for HIV and in effective treatments for HIV, NIDA has revised its 2001
policy on HIV counseling and testing. NIDA-funded researchers are strongly
encouraged to provide and/or refer research subjects to HIV risk reduction
education and education about the benefits of HIV treatment, counseling and
testing, referral to treatment, and other appropriate interventions to prevent
acquisition and transmission of HIV. This policy applies to all NIDA funded research
conducted domestically or internationally. For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended
Guidelines for the Administration of Drugs to Human Subjects: The National
Advisory Council on Drug Abuse (NACDA) recognizes the importance of research
involving the administration of drugs with abuse potential, and dependence or addiction
liability, to human subjects. Potential applicants are encouraged to obtain
and review these recommendations of Council before submitting an application
that will administer compounds to human subjects. The guidelines are available
on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects

Data Harmonization for Substance Abuse and Addiction via the
PhenX Toolkit: NIDA strongly encourages investigators involved in
human-subjects studies to employ a common set of tools and resources that will
promote the collection of comparable data across studies and to do so by
incorporating the measures from the Core and Specialty collections, which are
available in the Substance Abuse and Addiction Collection of the PhenX Toolkit
(www.phenxtoolkit.org). Please see NOT-DA-12-008 (http://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html)
for further details.

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or
both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Renewal
Resubmission
Revision

The OER
Glossary and the SF424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations
and the submission of a sufficient number of meritorious applications.

Award Budget

Direct costs are limited to $275,000 over a two-year
period, with no more than $200,000 in direct costs allowed in any single
year. Application budgets should reflect the actual needs of the proposed
project.

Award Project Period

The maximum project period is two years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. The NIH
Policy on Late Submission of Grant Applications states that failure to
complete registrations in advance of a due date is not a valid reason for a
late submission.

Dun and Bradstreet
Universal Numbering System (DUNS) - All registrations require that
applicants be issued a DUNS number. After obtaining a DUNS number, applicants
can begin both SAM and eRA Commons registrations. The same DUNS number must be
used for all registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants
must have an active DUNS number and SAM registration in order to complete the
Grants.gov registration.

Program
Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should
work with their organizational officials to either create a new account or to
affiliate an existing account with the applicant organization’s eRA Commons
account. If the PD/PI is also the organizational Signing Official, they must
have two distinct eRA Commons accounts, one for each role. Obtaining an eRA
Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all
applicable components, required and optional. Please note that some components
marked optional in the application package are required for submission of
applications for this FOA. Follow all instructions in the SF424 (R&R)
Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

The following section supplements the instructions found in
the SF424 (R&R) Application Guide and should be used for preparing an
application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide
must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Appendix:
Do not use the Appendix to circumvent page limits. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions
for completing Planned Enrollment Reports as described in the SF424 (R&R)
Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions
for completing Cumulative Inclusion Enrollment Report
as described in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies
described in the NIH Grants
Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the due date to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants
across all Federal agencies). Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration. NIH and Grants.gov systems check the application against many
of the application instructions upon submission. Errors must be corrected and a
changed/corrected application must be submitted to Grants.gov on or before the application
due date. If a Changed/Corrected application is submitted after the deadline,
the application will be considered late.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management. Additional information may be
found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review, NIH. Applications that are
incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

For this FOA, please note the following:

The R21 exploratory/developmental
grant supports investigation of novel scientific ideas or new model systems,
tools, or technologies that have the potential for significant impact on
biomedical or biobehavioral research. An R21 grant application need not have
extensive background material or preliminary information. Accordingly,
reviewers will focus their evaluation on the conceptual framework, the level of
innovation, and the potential to significantly advance our knowledge or
understanding. Appropriate justification for the proposed work can be provided
through literature citations, data from other sources, or, when available, from
investigator-generated data. Preliminary data are not required for R21
applications; however, they may be included if available.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves human subjects and/or NIH-defined clinical research,
are the plans to address 1) the protection of human subjects from research
risks, and 2) inclusion (or exclusion) of individuals on the basis of
sex/gender, race, and ethnicity, as well as the inclusion or exclusion of
children, justified in terms of the scientific goals and research strategy
proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Guidelines
for the Review of Human Subjects.

Inclusion of Women, Minorities, and
Children

When the proposed project involves human subjects
and/or NIH-defined clinical research, the committee will evaluate the proposed
plans for the inclusion (or exclusion) of individuals on the basis of
sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of
children to determine if it is justified in terms of the scientific goals and
research strategy proposed. For additional information on review of the
Inclusion section, please refer to the Guidelines
for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the environment,
and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the
project.

Renewals

For Renewals, the committee will consider the
progress made in the last funding period.

Revisions

For Revisions, the committee will consider the
appropriateness of the proposed expansion of the scope of the project. If the
Revision application relates to a specific line of investigation presented in
the original application that was not recommended for approval by the committee,
then the committee will consider whether the responses to comments from the
previous scientific review group are adequate and whether substantial changes
are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this
section of the application, including 1) the Select Agent(s) to be used in the
proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), at the Center for
Scientific Review in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Applications will be assigned on the basis of established
PHS referral guidelinesto the appropriate NIH Institute or Center. Applications
will compete for available funds with all other recommended applications. Following
initial peer review, recommended applications will receive a second level of
review by the appropriate national Advisory Council or Board. The following
will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the NIH Grants
Policy Statement.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.